Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase: A twenty‐eight–day, multicenter, phase II, randomized, double‐blind, placebo‐controlled, dose‐response clinical trial examining safety and efficacy in patients with gout

Abstract

Objective. Gout affects ϳ1-2% of the American population. Current options for treating hyperuricemia in chronic gout are limited. The purpose of this study was to assess the safety and efficacy of febuxostat, a nonpurine selective inhibitor of xanthine oxidase, in establishing normal serum urate (sUA) concentrations in gout patients with hyperuricemia (>8.0 mg/dl).Methods. We conducted a phase II, randomized, double-blind, placebo-controlled trial in 153 patients (ages 23-80 years). Subjects received febuxostat (40 mg, 80 mg, 120 mg) or placebo once daily for 28 days and colchicine prophylaxis for 14 days prior to and 14 days after randomization. The primary end point was the proportion of subjects with sUA levels <6.0 mg/dl on day 28.Results. Greater proportions of febuxostattreated patients than placebo-treated patients achieved an sUA level <6.0 mg/dl at each visit (P < 0.001 for each comparison). The targeted sUA level was attained on day 28 in 0% of those taking placebo and in 56% of those taking 40 mg, 76% taking 80 mg, and 94% taking 120 mg of febuxostat. The mean sUA reduction from baseline to day 28 was 2% in the placebo group and 37% in the 40-mg, 44% in the 80-mg, and 59% in the 120-mg febuxostat groups. Gout flares occurred with similar frequency in the placebo (37%) and 40-mg febuxostat (35%) groups and with increased frequency in the higher dosage febuxostat groups (43% taking 80 mg; 55% taking 120 mg). During colchicine prophylaxis, gout flares occurred less frequently (8-13%). Incidences of treatment-related adverse events were similar in the febuxostat and placebo groups.Conclusion. Treatment with febuxostat resulted in a significant reduction of sUA levels at all dosages. Febuxostat therapy was safe and well tolerated.Uric acid is the end product of purine degradation in humans. Hyperuricemia, a serum concentration of urate that exceeds the limit of urate solubility (ϳ7.0 mg/dl), is a common biochemical abnormality (1). Aberrations in any of the multiple mechanisms involved in the production and/or excretion of uric acid may increase serum urate (sUA) concentrations, and persistent hyperuricemia is a marker of monosodium urate (MSU) supersaturation in extracellular fluid (2). As such, hyperuricemia is a necessary (but often not sufficient) risk factor for MSU crystal deposition in tissues, the fundamental pathophysiologic process underlying the clinical manifestations of gout (3). Gout can thus be defined as MSU crystal deposition disease.

Pneumocystic Pneumonia in Rheumatic Diseases: Current Issues in Prophylaxis

“…Первые впечатляющие результаты, демонстрирующие высокую вероятность достижения целевого уровня МК, были получены в рамках II фазы клинических исследова-ний препарата [31]. В исследовании приняли участие 153 пациента с подагрой и исходным сывороточным уровнем МК в крови >480 мкмоль/л (>8,0 мг/дл).…”

The Real World of Gout

“…Benzbromarone has been shown to have an efficacy of 78 to 92% for achieving a serum urate < 300 µmol/l in RCT, which increases to 100% in non-randomized settings 14 . Febuxostat has an efficacy of 53 to 94% for achieving a serum urate < 360 µmol/l in RCT 12,16 . To my knowledge there are scarce published data on the real-world efficacy of febuxostat.…”

Gout and Quality of Life: Table 1.

“…These findings support the notion that clinical disease outcomes, and not SUA levels, are meaningful for the quality of life in patients with gout. While the initial clinical trials for new urate-lowering agents employ SUA levels as endpoints for several logistic reasons [18][19][20]22,23 , more direct evidence demonstrating that these new drugs lead to improved clinical measures (e.g., gout flares, HRQOL) should be sought in future research.…”

“…Recent studies indicate that the majority of gout patients under the care of physicians are not adequately managed with currently available anti-gout therapies [13][14][15][16][17] . These gout cases have been referred to as "treatment-failure gout" and have become the primary target for quality improvement of care, including new drug development 13,[18][19][20][21][22][23] . Although recent treatment guidelines and increased educational efforts could improve the quality of gout care, even under the very best of conditions, between 100,000 and 300,000 in the US are expected to be classified as "treatment-failure gout" cases with currently available anti-gout therapies 13 .…”